Worldwide, breast cancer is the second most common type of cancer and one of the most common causes of cancer death in humans. It is the most common cancer in women. Breast cancer is a heterogeneous disease that is treated by surgery, chemotherapy and several rationale-based targeted therapies. The choice of optimal course of treatment depends on the availability of biomarkers, which are measured by appropriate clinical assays. Unfortunately, at the present very few useful biomarkers have been identified and translated to clinical use. These are the oestrogen receptor (ER), progesterone receptor (PR) and the ErbB2 receptor. These three markers are very useful but about a third of diagnosed cases are triple-negative. In other words, the tumours do not express ER, PgR and Her2. For this type of breast cancer new biomarkers and diagnostic and prognostic assays are in high demand.
Cancer metastasis is a multistage process that is governed by a complex program of gene expression and signal transduction that ultimately allows the metastasizing cells to invade surrounding stroma, travel through the circulation, and colonize distant sites. This program sequentially switches specific genes on and turns others off, effectively exerting very dramatic changes of the abundance of many hundreds of proteins in the cell. Since the completion of the human genome project, post-genomic approaches based on application of oligonucleotide microarrays and next-generation sequencing are beginning to shed light on the global cancer genomics landscape and its molecular landmarks.
In addition, developments in quantitative proteomics now allow us to dig even deeper: to map the posttranslational modifications and protein-protein interactions that are at the core of the regulation of the molecular mechanisms that drive metastasis. Here I describe one such quantitative proteomics approach to investigate the role of CD74 in promoting metastasis of triple-negative breast cancer, a particularly malignant type of the disease.
CD74, the γ subunit of the major histocompatibility complex (MHC) class II complex, is frequently overexpressed in malignant tumors of epithelial and mesenchymal origin. The protein has been suggested as a potential target for rationale-based therapies of lymphoma and multiple myeloma and therapeutic agents targeting CD74 or components of its signaling cascade are in advanced stages of clinical development [1-3]. More recently, I and others reported that CD74 overexpression is linked to increased invasion and metastasis of breast tumors, particularly the tumors of the triple-negative phenotype [4,5]. CD74 is a chaperone protein with an important role in innate immunity. It is required for the expression and functions of the MHC class II receptors and, in addition, has been implicated in cytokine and survival signaling [6-8]. However, the mechanistic foundation for the apparent CD74-augmented malignancy of triple-negative breast tumors is not known. To address this, I have engineered human epithelial cells to express CD74 under the control of a highly regulated inducible promoter, which allowed us to study the effect of CD74 overexpression on protein abundance and protein phosphorylation at a system-wide scale.
I have surprisingly identified that when overexpressed, CD74 affects the phosphorylation state and function of Scribble, a product of the well-known tumor suppressor gene scrib, which is crucial for the proper maintenance of epithelial cell integrity and function and which is frequently deregulated in breast cancer [9]. Scribble function in maintaining polarity was first discovered in Drosophila. Bilder et al. found that scrib mutations cause aberrant cell shape and loss of monolayer organization in epithelia [10] and that scrib acts as a tumor suppressor [11]. In human cells, Scribble is required for E-cadherin-mediated cell-cell adhesion, and when its expression is downregulated, epithelial cells acquire mesenchymal appearance and their migration is augmented [12].
The invention is aimed at providing methods for the detection and prognosis of cancer, in particular epithelial cancer.